Bottom Line:
Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling.AR directly interacts with the MLL complex via the menin-MLL subunit.Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice.

ABSTRACTResistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.

Mentions:
Given the importance of the MLL complex in solid tumors23–25, we examined menin expression in a set of human prostate cancer tissue samples. Using RNA-Seq we observed that menin expression was associated with disease progression with significantly elevated levels in metastatic prostate cancer compared to hormone naïve prostate cancer and benign prostate (Fig. 5a). We validated this observation using prostate cancer samples from The Cancer Genome Atlas (TCGA); that also demonstrated menin up-regulation in prostate cancer compared to benign controls (Fig. 5b). Notably, among other members of the MLL complex, while WDR5 transcript levels was elevated in metastatic prostate cancer MLL, MLL4, ASH2L and RBBP5 were not differential (Supplementary Fig. 8a–e). We next analyzed expression of menin in published microarray datasets using the Oncomine database29. Similar to the RNA-Seq data, menin expression was elevated in localized and metastatic prostate cancer in multiple published studies (Fig. 5c–d). Similarly, Menin protein was also elevated in during prostate cancer progression, with notably higher protein levels in metastatic compared to localized disease (Fig. 5e).

Mentions:
Given the importance of the MLL complex in solid tumors23–25, we examined menin expression in a set of human prostate cancer tissue samples. Using RNA-Seq we observed that menin expression was associated with disease progression with significantly elevated levels in metastatic prostate cancer compared to hormone naïve prostate cancer and benign prostate (Fig. 5a). We validated this observation using prostate cancer samples from The Cancer Genome Atlas (TCGA); that also demonstrated menin up-regulation in prostate cancer compared to benign controls (Fig. 5b). Notably, among other members of the MLL complex, while WDR5 transcript levels was elevated in metastatic prostate cancer MLL, MLL4, ASH2L and RBBP5 were not differential (Supplementary Fig. 8a–e). We next analyzed expression of menin in published microarray datasets using the Oncomine database29. Similar to the RNA-Seq data, menin expression was elevated in localized and metastatic prostate cancer in multiple published studies (Fig. 5c–d). Similarly, Menin protein was also elevated in during prostate cancer progression, with notably higher protein levels in metastatic compared to localized disease (Fig. 5e).

Bottom Line:
Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling.AR directly interacts with the MLL complex via the menin-MLL subunit.Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice.

ABSTRACTResistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.